Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• the present invention relates to pyrazolopyridines having useful pharmacological activity, to a process for their preparation and to their use as pharmaceuticals.
• European Patent Publication No. 119774 discloses a group of pyrazolopyridine derivatives which are described as of potential use as anti-inflammatories.
• the present invention provides a compound of the formula (I) and pharmaceutically acceptable salts and solvates thereof: wherein:
• Suitable values for X include those wherein R in NR is hydrogen, methyl, ethyl, n-and iso-propyl, preferably hydrogen; and oxygen or sulphur.
• R in NR is hydrogen, methyl, ethyl, n-and iso-propyl, preferably hydrogen; and oxygen or sulphur.
• Favourably X is NH.
• Suitable values for R 1 /R 2 include hydrogen, methyl, ethyl, n -and iso-propyl, aminomethyl optionally N-substituted, and acetamidomethyl and acetyl, or together forming C 3 or C 4 polymethylene.
• Suitable values for R 3 include methyl, ethyl, n-and iso-propyl, n-, iso -sec-and tert-butyl, n-pentyl, (CH 2 ) n CH 3 wherein n is 4 to 7 , or cyclohexyl, optionally substituted by methyl, ethyl and/or hydroxy, methoxy, n-or iso-propoxy, thiol, methylthio or amino optionally substituted by one or two methyl or acetyl groups or by C 4 or C 5 polymethylene; vinyl, prop-1-enyl, prop-2-enyl, 1-methylvinyl, but-1-enyl, but-2-enyl, but-3-enyl, 1-methylenepropyl, 1-methylprop-1-enyl and 1-methylprop-2-enyl in their E and Z forms where stereoisomerism exists; or phenyl optionally substituted by one or two chloro, bromo,
• R 3 More suitable values for R 3 include n-butyl, n-pentyl, allyl or prop-2-enyl, 2-methylallyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 3-diethylaminopropyl, phenyl and phenyl substituted by one of hydroxy, nitro, cyano, carboxy, t-butyl and ethoxycarbonyl in the 3-or 4-position.
• Favourable values for R 3 include n-butyl, prop-2-enyl and 2-hydroxyethyl, 3-dimethylaminopropyl and 3-diethylaminopropyl.
• R include hydrogen, methyl, ethyl, n-and iso-propyl and benzyl. More suitably R 4 is hydrogen or 2-methyl. Favourably R4 is hydrogen.
• R 4 is hydrogen the compounds of formula (I) exist as tautomers, i.e. the R 4 hydrogen atom is labile.
• the compounds wherein R 4 is hydrogen are therefore of formulae (Ila) and (IIb).
• the compounds of the formula (I) can form acid addition salts with acids, such as the conventional pharmaceutically acceptable acids, for example hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulphonic.
• acids such as the conventional pharmaceutically acceptable acids, for example hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulphonic.
• acids such as the conventional pharmaceutically acceptable acids, for example hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulphonic.
• Such compounds form part of the present invention, as do solvates, for example hydrates, of the compounds of formula (I) or salts thereof.
• R is hydrogen or C 1-6 alkyl
• R 2 is CN, CR 5 R 6 Y'wherein Y'is OR 7 , SR, or NR 8 R 9 , or COR 10 ; or R 2 is as defined for R 1 or phenyl optionally substituted as defined in formula (I); and R, is CN, CR 5 R 6 Y or COR 10 ; and wherein Y, R 5 , R 6 ,R 7 ,R 8 ,R 9 ,R 10 and the remaining variables are as defined in formula (I).
• R 4 when other hydrogen is preferably attached at nitrogen atom 2.
• R 18 is hydrogen, chloro, bromo, methoxy, ethoxy, hydroxy, cyano, carboxyl, ethoxycarbonyl, nitro or t-butyl.
• R 18 when other than hydrogen is attached at the 3-or 4-position, most preferably the 4-position.
• a preferred sub-group of compounds within formula - (III) is of formula (V): wherein R 3 1 is n -butyl, iso-butyl, allyl, 2-hydroxyethyl, 3-dimethylaminopropyl, or 3-diethyl-aminopropyl, and R,' and R 4 1 are as defined in formula (III).
• a further group of compounds within formula (I) is of formula (VI): wherein R 2 1 is CN, CR 5 R 6 Y'or COR 10 as defined and the remaining variables are as defined in formula (III).
• R 2 1 , R', R, and R 4 1 are as described for the relevant variables under formula - (I).
• a preferred sub-group of compounds within formula - (VI) is of formula (VII): wherein R 3 1 and R 4 1 are as defined in formula (V) and R 2 1 is as defined in formula (VI).
• Suitable and preferred values for X', R,', R 3 and R 4 1 are as described for the relevant variables under formula - (I).
• Another group of compounds within formula (1) is of formula (IX): in which n is 3 to 8 and R,, is hydrogen or C 1 -C 4 alkyl, and X, R 3 and R 4 are as defined for formula (I)
• a preferred sub-group of compounds within formula - (X) is of formula (X): in which R 3 1 and R 4 1 are as defined for formula (V) and m is 1 or 2.
• the present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, which process comprises the reaction of a compound of formula (XI): wherein Q is a leaving group, R 1 ' and R 2 ' are R, and R 2 as defined in formula (1) or atoms or groups convertible thereto and R 4 ' is R 4 as defined in formula (I)or an atom or group convertible thereto, with a compound of formula (XII): HX 2 R 3 ' (XII) wherein X 2 is NR (as defined in formula (I)), oxygen or sulphur and R 3 ' is R 3 or a group or atom convertible thereto; and thereafter optionally and as necessary converting X 2 to X, R 1 ' to R 1, R 2 'to R 2, R 3 ' to R 3 and/or R 4 ' to R 4, and/or forming a pharmaceutically acceptable salt or solvate thereof.
• one compound of formula (I) may be converted to another compound of formula (I) by interconversion of suitable substituents.
• certain compounds of formula (I) are useful intermediates in forming other compounds of the present invention.
• salts or solvates of the compounds of formula (I) which are not pharmaceutically acceptable may be useful is intermediates in the production of pharmaceutically acceptable salts or solvates. Accordingly such salts or sol- vates also form part of this invention.
• Suitable leaving groups Q include halogens such as chloro and bromo, preferably chloro.
• the reaction may be carried out under conventional conditions for nucleophilic aromatic displacements, at ele- rated temperatures using excess of reagent as solvent (eg aniline when X is NR) or in an inert solvent such as :oluene, ethanol, dimethylformamide, dimethylsulphoxide, jioxan or water.
• solvent eg aniline when X is NR
• inert solvent such as :oluene, ethanol, dimethylformamide, dimethylsulphoxide, jioxan or water.
• the reaction preferably takes place in a sealed tube if HX 2 R 3 ' is of low boiling point
• the reac- lion may take place in the presence of a base, such as sodium hydride, potassium t-butoxide or sodium t-butoxide.
• Compounds of formula (I) wherein X is SO or SO 2 may be prepared from the corresponding compounds wherein X is S by conventional oxidation methods, such as using sodium periodate or with one equivalent of m-chloroperbenzoic acid (to form the compound of formula (I) wherein X is SO) or two equivalents of m-chloroperbenzoic acid (to form the compound of formula (I) wherein X is SO 2 ).
• Conversion of an R hydrogen in X to an R C 1-6 alkyl group may be carried out by conventional amine alkylation or acylation (e.g. formylation) followed by reduction.
• R 1 '/R 2 'to R,/R may be carried out by conventional functional group interchanges.
• R 1 '/R 2 'to R,/R may be carried out by conventional functional group interchanges.
• R,' or R 2 ' may be methyl, in which case it may be converted to a C0 2 H group by conventional oxidation with an oxidising agent such as potassium permanganate. This conversion is preferably, however, carried out on the intermediate of formula (XI) or at an earlier stage.
• An CO,H group in R,' or R 2 ' may be converted to an alkoxycarbonyl group by conventional esterification procedures or to an amide group by condensation and in the presence of a dehydrating agent, such as dicyclohexylcarbodiimide.
• R,'or R,' group when amide can be converted to an ester group by conventional hydrolysis/esterification in ethanolic HCI. It will be appreciated that when R,'or R; is an ester group, reaction of the compound of formula (XII) with the compound of formula (XI) may also substitute the ester to give an amide.
• R 4 hydrogen atom may be converted to an R 4 C 1- 6 alkyl group by conventional alkylation procedures.
• compositions of formula (I) may be formed conventionally by reaction with the appropriate acid, and solvates by crystallization from the appropriate solvent.
• compounds of the formula (XI) wherein Q is chloro may be prepared by the phosphorus oxychloride chlorination of a compound of formula (XIII):
• the invention provides a pharmaceutical composition which comprises a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.
• compositions may be adapted for administration via the topical, oral, rectal or injection routes.
• the compositions of this invention may be prepared by admixture of the active ingredient with the carrier, such as diluents, binder, fillers, disintegrants, flavouring agents, colouring agents, lubricants, preservatives, in conventional manner.
• the carrier such as diluents, binder, fillers, disintegrants, flavouring agents, colouring agents, lubricants, preservatives, in conventional manner.
• these conventional excipients may be employed in conventional manner, for example as in the preparation of compositions of ketoprofen, indomethacin, naproxen, acetylsalicylic acid or other anti-inflammatory agents.
• the compounds of the invention have topical anti-inflammatory activity and therefore will normally be made up into a composition which is a cream, totion, liniment, get, gel stick, ointment, spray or aerosol for topical administration to the skin.
• Cream, lotion, liniment, get, gel stick, ointment, spray and aerosol formulations that may be used for compounds of the formula (I) are conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics and cosmetics, such as Harry's Cos- meticology published by Leonard Hill Books, Remington's Pharmaceutical Sciences, and the British and US Pharmacopoeias- A standard emulsifying ointment base or anhydrous polyethylene glycol are simple examples of such suitable formulations.
• oils suitable for inclusion in a standard emulsifying ointment base include mineral oils, vegetable oils, synthetic fatty acid esters, fatty alcohols, lanolin and its derivatives.
• compositions will normally include a suitable emulsifier.
• the composition can range from liquid through semi-liquid to gel types according to the type of emulsion and quantity of any thickening agent which may be present
• emulsifiers include polyhydric alcohol esters such as sorbitan monostearate, fatty acid esters such as glyceryl monostearate, and polyester derivatives of fatty acids or fatty alcohols.
• compositions may also contain anti-oxidants and other conventional ingredients such as preservatives, perfumes and alcohol.
• a penetrating agent such as AZONE may also be included.
• compositions for topical treatment may also contain other therapeutic agents such as anti-infective and/or anti-viral agents.
• Suitable anti-infective agents include the topically applicable antibacterial, anti-yeast, anti-fungal and anti-herpes agents.
• compositions may be used in the topical treatment of atopic and contact dermatitis, psoriases, acne, eczema and other inflammatory dermatoses and inflammatory conditions of eyes, ears, nose and throat Treatment of inflammation of the skin may, however, also be carried out utilising an oral composition of the invention, as hereinbefore described.
• the amount of compound of the formula (1) used will depend on a number of factors such as the nature and severity of the disorder being treated, and the specific compound being used. However, by way of illustration it is believed that effective therapy can be achieved using roughly similar amounts of the compounds of formula (I) as would be used of hydrocortisone.
• a typical formulation will suitably contain 0.1 to 20%, more suitably 0.5 to 5% of the compound of formula (I).
• a composition of this invention is useful in the treatment of rheumatism and arthritis and in the treatment of pain and other inflammatory conditions and also in the treatment of the prophylaxis of bronchial asthma, rhinitis, hay fever and allergic eczema.
• the oral compositions of this invention will be in the form of a unit dose such as a tablet, capsule or reconstitutable powder in a sachet
• Such unit doses will generally contain from 10 mg to 1000 mg and more suitably will contain from about 30 mg to 500 mg for example 50 mg to 250 mg of active agent, for example about 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 mg.
• compositions may be administered once or more times a day, for example 2,3 or 4 times daily, so that the total daily dose for a 70 kg adult will usually be in the range of 20 to 3000 mg and more usually in the range of 40 to 1 000 mg.
• the unit dose may contain from 2-20 mg of active agent and may be administered in multiples if desired to give the preceeding daily dose.
• a suitable dosage unit may contain 0.01 to 500 mg of active ingredient, more suitably 1 to 500 mg for use via the oral route, 0.01 to 10 mg-viainhalation, which is preferred.
• the effective dose of compound depends on the particular compound employed, the condition of the patient and the frequency and route of administration, but in general is in the range of from 0.001 mg/day to 100 mg/day per kilogram of the patient's body weight.
• small amounts of other anti-asth- matics and bronchodilators for example sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; xanthine derivatives such as theophylline and aminophylline and corticosteroids such as prednisolone and adrenal stimulants such as ACTH may be included.
• sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine
• xanthine derivatives such as theophylline and aminophylline and corticosteroids such as prednisolone and adrenal stimulants such as ACTH
• ACTH adrenal stimulants
• a favoured form of oral composition of this invention is a tablet containing the active agent.
• the active agent may be in the form of a recompressed granulate of the active ingredient in intimate mixture with a lubricant such as magnesium stearate, a filler such as microcrystalline cellulose and a disintegrant such as sodium starch glycollate.
• a particular composition of the invention for inflammatory diseases is a hard gelatin capsule containing the required amount of a compound of the invention in the form of a powder or granulate in intimate mixture with a lubricant such as magnesium stearate, a filler, such as microcrystalline cellulose, and a disintegrant, such as sodium starch glycollate.
• a lubricant such as magnesium stearate
• a filler such as microcrystalline cellulose
• a disintegrant such as sodium starch glycollate.
• Preparations especially suitable for administration to the respiratory tract include, for example, a snuff, an aerosol, a solution for a nebulizer, or a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
• the particles of active compound suitably have diameters of less than 50 microns, preferably less than 10 microns.
• fluid unit dosage forms are prepared utilising a compound of the formula (I) or pharmaceutically acceptable salt thereof and a sterile vehicle.
• the compound depending on the "vehicle and concentration used, can be either suspended or dissolved in the vehicle.
• the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
• adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
• Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
• a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
• the invention further provides a method of treatment or prophylaxis of inflammatory and/or allergic conditions in mammals including man which comprises the administration of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof to the sufferer.
• the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in treating disorders in mammals, and in particular inflammatory and/or allergic conditions.
• the invention also provides the use of a compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for , treating inflammatory and/or allergic conditions.
• Mammals which may be thus treated include humans and domestic animals such as dogs, cats or horses.
• the medicament will be administered orally as 1, 3 or 4 doses per day at the dose level previously indicated.
• Ethyl 7-chloro-7Hpyrazolo[4,3-b]pyridine-6-carboxylate (2.2 5 g, 0.0 1 mole) and allylamine (20ml) were stirred together overnight at room temperature. The excess allylamine was removed under reduced pressure. The residue was dissolved in the minimum volume of aqueous ethanol and sufficient 10% sodium carbonate added to give pH 8.
• Ethyl 7-allylamino-1H-pyrazolo[4,3-b]pyridine-6-carboxylate (5.0g, 20mmol) was added to a solution of sodium hydroxide (2.4g, 60mmol) in water (100ml) and heated under reflux for 60 min. The solution was filtered, diluted with water (200ml) and made neutral with 5 N hydrochloric acid. The solid was filtered off, washed with water and dried to give the title compound (4.25g, 96%), m.p. 2 4 0-2 4 2°C.
• the title compound was prepared from 4-nitropyrazole (5.2g, 0.0 4 6 mole) as in description 7, using ethyl 2-cyclopentanonecarboxylate to react with the amine.
• the product was obtained as a white solid (9.6g, 94%) m.p. 121-123°C.
• the title compound was prepared from ethyl 2-(pyrazol-4-ylamino)cyclopentene-1-carboxylate (9.4g, 0.042 mole) using the method of description 8.
• the product was obtained as a beige solid (6.2g, 84%)m.p. >310°C.
• the title compound was prepared from 4,5,6,7,8-pentahydro-8-oxo-1H-cyclopenta[b]pyrazolo[3,4-e]pyridine - (6.0g, 0.034 mole) using the method of description 9.
• the product was obtained as a white solid (5.9g, 89%) m.p. 210-213°C.
• Ethyl 2-acetyl-3-(4-pyrazolylamino)acrylate (D13, 1.0g, 4.5 mmol) was added to boiling Dowtherm A, and the solution was heated under reflux for 20 min. The mixture was allowed to cool and 60-80° petroleum ether (100 ml) was added. The solid was filtered off and washed well with petroleum ether to give the title compound (590 mg, 74%), m.p. >320°C.
• Ethyl 7-chloro-i H-pyrazolo[4,3-b]pyridine-6-carboxylate (3.5g, 15.5 mmol) was dissolved in n-butylamine (25ml) and stirred at room temperature for 3h. Excess butylamine was removed in vacuo and the residual solid was washed well with water, and recrystallised from ethyl acetate to give ethyl 7-n-butyiamino-1H-pyrazolo[4,3-b]pyridine-6-carboxylate (2.75g, 67%),m.p. 164-770°C.
• Trifluoroacetic anhydride (1.91ml, 13.5mmol) was added dropwise to an ice-cooled, stirred suspension of 7- allylamino-1H-[4,3-b]pyridine-6-carboxamide (1.4g, 6.45mmol) in dry dioxane (10ml) and pyridine (1.6ml, 19.3mmol). The mixture was stirred at room temperature overnight, water was added and the pH was adjusted to pH 9 with 10% sodium carbonate solution. The solid was filtered off, and the aqueous solution was extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO 4 ) and evaporated in vacuo. The residue was crystallised from ethanol/ethyl acetate to give the title compound - (260mg, 20%), m.p. 2 4 9-252°C.
• the title compound was prepared from 8-chloro-5,6,7-trihydro-1 H-cyclopenta[b]pyrazolo[3,4-e]pyridine (3.0g, 0.016 mole) using the method of example 5.
• the product was recrystallised from ethyl acetate/methanol to give a beige solid (1.27g, 38%) m.p. 232-235°C.
• the product was purified by column chromatography on basic alumina eluting with 20% methanol/ethyl acetate.
• the title compound was obtained as a beige solid after recrystallisation from ethyl acetate (1.20g, 37%) m.p. 148-150°C.
• 0.2 ml of a 2.0% solution of X-carrageenin (Viscarin 402) in saline was injected intrapleurally in anaesthetised rats (wt. approx. 175-200g). Compounds were administered 1 hour before carrageenin and at 24 and 48 hours after carrageenin. 72 hours after carrageenin injection, 4.0 ml of EDTA solution (5 g EDTA in 100 ml of 0.9% saline and 325 mg phenol red added together with saline to 1 litre) was injected intrapleurally after killing the animals, and the exudate was removed with a syringe through the diaphragm.
• Exudate volume was calculated from the dilution of the phenol red injected, determined spectrophotometrically (560 nm) and cellular content estimated with a DNA assay [Karsten U. and Wollenberger A. Anal. Biochem. 77, 464-470, 1977].
• the Compound of Example 5 at a dose of 25mg/kg p.o. gave a 31% inhibition of DNA content and a 36% inhibition of exudate volume compared to control levels - (p ⁇ 0.05).
• mice were sensitized with oxazolone (2 mg in 20 ⁇ l EtOH) on a shaved area of the abdomen. 5 days later, the animals received 10 ⁇ l THF/MeOH (1:1 v/v) on the right ear and the test compound in the same solvent on the left ear. 1 hour later, the animals were challenged with 100 ⁇ g oxazolone in 10 ⁇ l acetone on each ear. Ear weights were measured 2 4 hours later.
• Percentage inhibition of the inflammatory swelling refers to the increase in weight of left ears (oxazolone plus compound in THF/MeOH) compared to untreated negative controls, as a proportion of the increase in weight of right ears (oxazolone only in THF/MeOH) over similar controls.

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• 1986
  • 1986-02-17 EP EP86301089A patent/EP0193329A3/fr not_active Withdrawn
  • 1986-02-20 DK DK79986A patent/DK79986A/da not_active Application Discontinuation
  • 1986-02-20 AU AU53793/86A patent/AU5379386A/en not_active Abandoned
  • 1986-02-20 ES ES552241A patent/ES8801918A1/es not_active Expired
  • 1986-02-21 PT PT82072A patent/PT82072B/pt unknown
  • 1986-02-21 GR GR860508A patent/GR860508B/el unknown
• 1987
  • 1987-10-21 US US07/112,050 patent/US4837238A/en not_active Expired - Fee Related

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